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Aberrant DNA methylation associated with aggressiveness of gastrointestinal stromal tumour
  1. Yasuyuki Okamoto1,2,
  2. Akira Sawaki3,
  3. Seiji Ito4,
  4. Toshirou Nishida5,
  5. Tsuyoshi Takahashi6,
  6. Minoru Toyota7,
  7. Hiromu Suzuki8,
  8. Yasuhisa Shinomura8,
  9. Ichiro Takeuchi9,
  10. Keiko Shinjo1,10,
  11. Byonggu An1,
  12. Hidemi Ito11,
  13. Kenji Yamao3,
  14. Makiko Fujii1,
  15. Hideki Murakami1,
  16. Hirotaka Osada1,10,
  17. Hiromi Kataoka2,
  18. Takashi Joh2,
  19. Yoshitaka Sekido1,10,
  20. Yutaka Kondo1,12
  1. 1Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-Ku, Nagoya 464-8681, Japan
  2. 2Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
  3. 3Department of Gastroenterology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-Ku, Nagoya 464-8681, Japan
  4. 4Department of Gastroenterological surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-Ku, Nagoya 464-8681, Japan
  5. 5Department of Surgery, Police Hospital, 10-31 Kitayama-cho, Tennoji-ku, Osaka 543-0035, Japan
  6. 6Department of Surgery, Osaka General Medical Center, 3-1-56 Bandai-Higashi, Sumiyoshi-ku, Osaka 558-8558, Japan
  7. 7Department of Biochemistry, Sapporo Medical University, 291 South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan
  8. 8First Department of Internal Medicine, Sapporo Medical University, 291 South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan
  9. 9Department of Computer Science, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan
  10. 10Department of Cancer Genetics, Program in Function Construction Medicine, Nagoya, University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
  11. 11Division of Epidemiology and Prevention, Aichi Cancer Center, 1-1 Kanokoden, Chikusa-Ku, Nagoya 464-8681, Japan
  12. 12PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
  1. Correspondence to Dr Yutaka Kondo, Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan; ykondo{at}aichi-cc.jp

Abstract

Background and aims The majority of gastrointestinal stromal tumors (GISTs) have KIT mutations; however, epigenetic abnormalities that could conceivably potentiate the aggressiveness of GISTs are largely unidentified. Our aim was to establish epigenetic profiles associated with the malignant transformation of GISTs.

Methods Methylation of four tumor suppressor genes, RASSF1A, p16, CDH1, and MGMT was analyzed in GISTs. Additionally, genome-wide DNA methylation profiles were compared between small, malignant-prone, and malignant GISTs using methylated GpG island amplification microarrays (MCAM) in a training set (n=40). Relationships between the methylation status of genes identified by MCAM and clinical features of the disease were tested in a validation set (n=75).

Results Methylation of RASSF1A progressively increased from small to malignant GISTs. p16 was specifically methylated in malignant-prone and malignant GISTs. MCAM analysis showed that more genes were methylated in advanced than in small GISTs (average of 473 genes vs 360 genes, respectively, P=0.012). Interestingly, the methylation profile of malignant GISTs was prominently affected by their location. Two genes, REC8 and PAX3, which were newly-identified via MCAM analysis, were differentially methylated in small and malignant GISTs in the training and validation sets. Patients with methylation of at least REC8, PAX3, or p16 had a significantly poorer prognosis (P=0.034).

Conclusion Our results suggest that GIST is not, in epigenetic terms, a uniform disease and that DNA methylation in a set of genes is associated with aggressive clinical behavior and unfavorable prognosis. The genes identified may potentially serve as biomarkers for predicting aggressive GISTs with poor survivability.

  • Biomarker
  • cancer genetics
  • DNA methylation
  • gastrointestinal neoplasia
  • gastrointestinal stromal tumour
  • molecular pathology

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Footnotes

  • Funding This work is supported by grants-in-aid for cancer research from the Ministry of Health, Labour and Welfare and a grant from the Japan Society for the Promotion of Science.

  • Competing interests None to declare.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Aichi Cancer Center Review Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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